P1544: BONE MINERAL DENSITY REMAINS STABLE IN PYRUVATE KINASE DEFICIENCY PATIENTS RECEIVING LONG-TERM TREATMENT WITH MITAPIVAT
Authors: H. Al-Samkari, R. F. Grace, A. Glenthøj, O. Andres, W. Barcellini, F. Galactéros, K. H. M. Kuo, D. M. Layton, M. Morado Arias, V. Viprakasit, Y. Dong, F. Tai, L. Grekas, K. Khoja, S. Gheuens, B. McGee, J. B. Porter, E. J. van Beers
Journal: HemaSphere (2022)

Background: Hereditary pyruvate kinase (PK) deficiency results in chronic hemolysis that may lead to reduced bone mineral density (BMD). Mitapivat is an oral activator of PK in red blood cells (RBC) that improves hemoglobin concentration and reduces transfusion burden in patients (pts) with PK deficiency. Although mitapivat has mild aromatase inhibition effects, a study of pts with PK deficiency who were not regularly transfused showed that mitapivat did not appear to promote progression of BMD abnormalities for up to 56 months (mos). Aims: Report BMD over time in a broad PK deficiency population (independent of transfusion) receiving long-term treatment with mitapivat. Methods: This study included pts ≥18 years (yrs) with PK deficiency enrolled in DRIVE-PK (NCT02476916; N=52, Phase [Ph] 2), ACTIVATE (NCT03548220; N=80, Ph 3), ACTIVATE-T (NCT03559699; N=27, Ph 3), and the long-term extension (LTE) of ACTIVATE and ACTIVATE-T (NCT03853798). Pts in DRIVE-PK and ACTIVATE were not regularly transfused (≤3 RBC units and ≤4 transfusion episodes in the prior yr). Pts in ACTIVATE-T were regularly transfused (≥6 transfusion episodes in the prior yr). Data from 90 pts who received mitapivat for >12 mos were pooled from these trials along with pts from the LTE who elected to continue or crossover (if on placebo) to mitapivat. BMD changes were measured using dual-energy X-ray absorptiometry (DXA) scans at 3 locations (total femur [combined femoral neck and total hip], femoral neck, and spine). Based on DXA T-scores, pts were classified according to standard definitions: normal BMD (≥–1.0 at all locations), osteopenia (>–2.5 to <–1.0 at ≥1 locations), or osteoporosis (≤–2.5 at ≥1 locations). DXA scans were obtained locally for all studies and interpreted locally for DRIVE-PK and centrally for ACTIVATE, ACTIVATE-T, and the LTE. Scans were collected as follows: baseline (BL), between Week (Wk) 24 and 28, every 6 mos to Mo 30, then annually (DRIVE-PK); BL, Wk 24 (ACTIVATE); BL, Wk 16, Wk 40 (ACTIVATE-T); BL, every 24 wks to Wk 96, then every 48 wks (LTE). Results: 90 pts were assessed: median age 34.5 yrs (range 18–71); 50.0% female; median mitapivat exposure 20 mos (range 12.2–64.9); concomitant bisphosphonate medication, 8 pts (8.9%); prior medical history of fracture, 8 pts (8.9%); fractures/joint injuries during study period, 6 pts (6.7%). At BL, 24 pts (26.7%) had normal BMD, 48 pts (53.3%) had osteopenia, 16 pts (17.8%) had osteoporosis, and 2 pts (2.2%) were missing BL T-score data. At last BMD assessment (data cut-off 04Mar2021), 76/88 pts (86.4%) remained stable, 7 pts (8.0%) improved, and 5 pts (5.7%) worsened (Figure). At last assessment, 27 (30.0%), 46 (51.1%), and 17 (18.9%) of 90 pts had a T-score indicating normal BMD, osteopenia, and osteoporosis (Table). Of 24 pts with BL T-scores ≥–1.0, 21 pts remained stable, and 3 pts had worsening BMD. Of 48 pts with a BL T-score >–2.5 to <–1.0, 6 pts improved to a T-score for normal BMD, 40 pts remained stable, and 2 pts worsened. Of 16 pts with a BL T-score of ≤–2.5, 1 pt improved to a T-score of >–2.5 to <–1.0. Image:Summary/Conclusion: In this analysis, BMD remained largely stable over time in adults with PK deficiency receiving long-term mitapivat (up to 65 mos). Pts had substantially low BMD at BL which did not progress, and it is hypothesized that mitapivat may halt bone loss in pts with PK deficiency by decreasing hemolysis and ineffective erythropoiesis and stabilizing iron homeostasis. BMD data will continue to be monitored as part of the ongoing LTE study to further understand this process.